Welcome to the I Can't Sleep Podcast,
Where I help you drift off one fact at a time.
I'm your host,
Benjamin Boster,
And today's episode is about circadian rhythm.
A circadian rhythm,
Or circadian cycle,
Is a natural oscillation that repeats roughly every 24 hours.
Circadian rhythms can refer to any process that originates within an organism and responds to the environment.
Circadian rhythms are regulated by a circadian clock,
Whose primary function is to rhythmically coordinate biological processes so they occur at the correct time to maximize the fitness of an individual.
Circadian rhythms have been widely observed in animals,
Plants,
Fungi,
And cyanobacteria,
And there is evidence that they evolved independently in each of these kingdoms of life.
The term circadian comes from the Latin circa,
Meaning around,
And dias,
Meaning days.
Processes with 24-hour cycles are more generally called diurnal rhythms.
Diurnal rhythms should not be called circadian rhythms unless they can be confirmed as endogenous and not environmental.
Although circadian rhythms are endogenous,
They are adjusted to the local environment by external cues,
Called Zeitgebers,
From German Zeitgeber,
Literally meaning time-giver,
Which include light,
Temperature,
And redox cycles.
In clinical settings,
An abnormal circadian rhythm in humans is known as a circadian rhythm sleep disorder.
The earliest recorded account of a circadian process is credited to Theophrastus,
Dating from the 4th century BC,
Probably provided to him by report of Androsthenes,
A ship's captain serving under Alexander the Great.
In his book Periphoton Historia,
Or Enquiry into Plans,
Theophrastus describes a tree with many leaves like the rose,
And that this closes at night,
But opens at sunrise,
And by noon is completely unfolded.
And at evening again it closes by degrees and remains shut at night,
And the natives say that it goes to sleep.
The mentioned tree was much later identified as the tamarind tree by the botanist H.
Bretzel in his book on the Botanical Findings of the Alexandrian Campaigns.
The observation of a circadian or diurnal process in humans is mentioned in Chinese medical texts dated to around the 13th century,
Including the Noon and Midnight Manual and the mnemonic rhyme to aid in the selection of acupoints according to the diurnal cycle,
The day of the month,
And the season of the year.
In 1729,
French scientist Jean-Jacques Tortus de Marant conducted the first experiment designed to distinguish an endogenous clock from responses to daily stimuli.
He noted that 24-hour patterns in the movement of the leaves of the plant,
Mimosa pudica,
Persisted,
Even when the plants were kept in constant darkness.
In 1896,
Patrick and Gilbert observed that during a prolonged period of sleep deprivation,
Sleepiness increases and decreases with a period of approximately 24 hours.
In 1918,
J.
S.
Szymanski showed that animals are capable of maintaining 24-hour activity patterns in the absence of external cues,
Such as light and changes in temperature.
In the early 20th century,
Circadian rhythms were noticed in the rhythmic feeding times of bees.
Auguste Forel,
Ingeborg Belling,
And Oskar Wall conducted numerous experiments to determine whether this rhythm was attributed to an endogenous clock.
The existence of circadian rhythm was independently discovered in fruit flies in 1935 by two German zoologists,
Hans Kalmus and Irving Boehnig.
In 1954,
An important experiment reported by Colin Pitendree demonstrated that occlusion,
The process of pupa turning into adult Androsophila pseudo-obscura,
Was a circadian behavior.
He demonstrated that while temperature played a vital role in occlusion rhythm,
The period of occlusion was delayed,
But not stopped,
When temperature was decreased.
The term circadian was coined by Franz Halberg in 1959.
According to Halberg's original definition,
The term circadian was derived from circa,
About,
And dies,
Day.
It may serve to imply that certain physiologic periods are close to 24 hours,
If not exactly that length.
Herein,
Circadian might be applied to all 24-hour rhythms,
Whether or not their periods,
Individually or on the average,
Are different from 24 hours,
Longer or shorter,
By a few minutes or hours.
In 1977,
The International Committee on Nomenclature of the International Society of Chronobiology formally adopted the definition,
Circadian,
Relating to biologic variations or rhythms with a frequency of one cycle in 24 ± 4 hours.
Circa,
About,
Approximately,
And dies,
Day,
Or 24 hour.
Note,
Term describes rhythms within about 24-hour cycle length,
Whether they are frequency synchronized with,
Or are desynchronized or free-running from the local environmental timescale,
With periods of slightly,
Yet consistently different from 24 hour.
Ron Konopka and Seymour Benser identified the first clock mutation in Drosophila in 1971,
Naming the gene,
Period Gene,
The first discovered genetic determinant of behavioral rhythmicity.
The Period Gene was isolated in 1984 by two teams of researchers.
Konopka,
Jeffrey Hall,
Michael Rosbash,
And their team showed that the period locus is the center of the circadian rhythm,
And that the loss of period stops circadian activity.
At the same time,
Michael W.
Young's team reported similar effects of period,
And that the gene covers 7.
1 kilobase interval on the X chromosome,
And encodes a 4.
5 kilobase poly-A plus RNA.
They went on to discover the key genes and neurons in Drosophila's circadian system,
From which Hall,
Rosbash,
And Young received the Nobel Prize in Physiology or Medicine 2017.
Joseph Takahashi discovered the first mammalian circadian clock mutation using mice in 1994.
However,
Recent studies show that deletion of clock does not lead to a behavioral phenotype,
The animals still have normal circadian rhythms,
Which questions its importance in rhythm generation.
The first human clock mutation was identified in an extended Utah family by Chris Jones,
And genetically characterized by Ying Hu Fu and Louis Satachik.
Affected individuals are extreme morning larks,
With four-hour advanced sleep and other rhythms.
This form of familial advanced sleep phase syndrome is caused by a single amino acid change,
An S662 to G mutation in the human PER2 protein.
To be called circadian,
A biological rhythm must meet these three general criteria.
1.
The rhythm has an endogenously derived free-running period of time that lasts approximately 24 hours.
The rhythm persists in constant conditions,
I.
E.
Constant darkness,
With a period of about 24 hours.
The period of the rhythm in constant conditions is called the free-running period and is denoted by the Greek letter τ.
The rationale for this criterion is to distinguish circadian rhythms from simple responses to daily external cues.
A rhythm cannot be said to be endogenous unless it has been tested and persists in conditions without external periodic input.
In diurnal animals,
Active during daylight hours,
In general τ is slightly greater than 24 hours,
Whereas in nocturnal animals,
Active at night,
In general τ is shorter than 24 hours.
2.
The rhythms are entrainable.
The rhythm can be reset by exposure to external stimuli,
Such as light and heat,
A process called entrainment.
The external stimulus used to entrain a rhythm is called the zeitgeber or time-giver.
Travel across time zones illustrates the ability of the human biological clock to adjust to the local time.
A person will usually experience jet lag before entrainment of their circadian clock has brought it into sync with local time.
3.
The rhythms exhibit temperature compensation.
In other words,
They maintain circadian periodicity over a range of physiological temperatures.
Many organisms live at a broad range of temperatures,
And differences in thermal energy will affect the kinetics of all molecular processes in their cells.
In order to keep track of time,
The organism's circadian clock must maintain roughly a 24-hour periodicity despite the changing kinetics,
A property known as temperature compensation.
The Q10 temperature coefficient is a measure of this compensating effect.
If the Q10 coefficient remains approximately 1 as temperature increases,
The rhythm is considered to be temperature compensated.
Circadian rhythms allow organisms to anticipate and prepare for precise and regular environmental changes.
They thus enable organisms to make better use of environmental resources,
E.
G.
Light and food,
Compared to those that cannot predict such availability.
It has,
Therefore,
Been suggested that circadian rhythms put organisms at a selective advantage in evolutionary terms.
However,
Rhythmicity appears to be as important in regulating and coordinating internal metabolic processes as in coordinating with the environment.
This is suggested by the maintenance,
Heritability of circadian rhythms in fruit flies after several hundred generations in constant laboratory conditions,
As well as in creatures in constant darkness in the wild,
And by the experimental elimination of behavioral,
But not physiological,
Circadian rhythms in quail.
What drove circadian rhythms to evolve has been an enigmatic question.
Previous hypotheses emphasize that photosensitive proteins and circadian rhythms may have originated together in the earliest cells,
With the purpose of protecting replicating DNA from high levels of damaging ultraviolet radiation during the daytime.
As a result,
Replication was relegated to the dark.
However,
Evidence for this is lacking.
In fact,
The simplest organisms with a circadian rhythm,
The cyanobacteria,
Do the opposite of this.
They divide more in the daytime.
Recent studies instead highlight the importance of coevolution of redox proteins with circadian oscillators in all three domains of life,
Following the Great Oxidation Event approximately 2.
3 billion years ago.
The current view is that circadian changes in environmental oxygen levels and the production of reactive oxygen species,
ROS,
In the presence of daylight,
Are likely to have driven a need to evolve circadian rhythms to preempt and therefore counteract damaging redox reactions on a daily basis.
The simplest known circadian clocks are bacterial circadian rhythms,
Exemplified by the prokaryote cyanobacteria.
Recent research has demonstrated that the circadian clock of Cynococcus elongatus can be reconstituted in vitro with just the three proteins of their central oscillator.
This clock has been shown to sustain a 22-hour rhythm over several days upon the addition of ATP.
Previous explanations of the prokaryotic circadian timekeeper were dependent upon a DNA transcription translation feedback mechanism.
A defect in the human homologue of the Drosophila period gene was identified as a cause of the sleep disorder FASPS,
Familial advanced sleep phase syndrome,
Underscoring the conserved nature of the molecular circadian clock through evolution.
Many more genetic components of the biological clock are now known.
Their interactions result in an interlocked feedback loop of gene products,
Resulting in periodic fluctuations that the cells of the body interpret as a specific time of the day.
It is now known that the molecular circadian clock can function within a single cell.
That is,
It is cell autonomous.
This was shown by Gene Block in isolated mollusc basal retinal neurons,
BRNs.
At the same time,
Different cells may communicate with each other,
Resulting in a synchronized output of electrical signaling.
These may interface with endocrine glands of the brain to result in periodic release of hormones.
The receptors for these hormones may be located far across the body and synchronize the peripheral clocks of various organs.
Thus,
The information of the time of the day is relayed by the eyes travel to the clock in the brain,
And through that,
Clocks in the rest of the body may be synchronized.
This is how the timing of,
For example,
Sleep-wake,
Body temperature,
Thirst,
And appetite,
Are coordinately controlled by the biological clock.
Circadian rhythmicity is present in the sleeping and feeding patterns of animals,
Including human beings.
There are also clear patterns of core body temperature,
Brain wave activity,
Hormone production,
Cell regeneration,
And other biological activities.
In addition,
Photoperiodism,
The physiological reaction of organisms to the length of day or night,
Is vital to both plants and animals,
And the circadian system plays a role in the measurement and interpretation of day length.
Timely predictions of seasonal periods of weather conditions,
Food availability,
Or predator activity is crucial for survival of many species.
Although not the only parameter,
A changing length of the photoperiod,
Day length,
Is the most predictive environmental cue for the seasonal timing of physiology and behavior,
Most notably for timing of migration,
Hibernation,
And reproduction.
Mutations or deletions of clock genes in mice have demonstrated the importance of body clocks to ensure the proper timing of cellular metabolic events.
Clock mutant mice are hyperphagic and obese,
And have altered glucose metabolism.
In mice,
Deletion of the REV-ERB-A-alpha clock gene can result in diet-induced obesity and changes the balance between glucose and lipid utilization,
Predisposing to diabetes.
However,
It is not clear whether there is a strong association between clock gene polymorphisms in humans and the susceptibility to develop the metabolic syndrome.
The rhythm is linked to the light-dark cycle.
Animals,
Including humans,
Kept in total darkness for extended periods,
Eventually function with a free-running rhythm.
Their sleep cycle is pushed back or forward each day,
Depending on whether their day,
Their endogenous period,
Is shorter or longer than 24 hours.
The environmental cues that reset the rhythms each day are called Zeitgebers.
Totally blind subterranean mammals are able to maintain their endogenous clock in the apparent absence of external stimuli.
Although they lack image-forming eyes,
Their photoreceptors,
Which detect light,
Are still functional.
They do surface periodically as well.
Free-running organisms that normally have one or two consolidated sleep episodes will still have them when in an environment shielded from external cues,
But the rhythm is not entrained to the 24-hour light-dark cycle in nature.
The sleep-wake rhythm may,
In these circumstances,
Become at a phase with other circadian or ultradian rhythms,
Such as metabolic,
Hormonal,
CNS electrical,
Or neurotransmitter rhythms.
Recent research has influenced the design of spacecraft environments as systems that mimic the light-dark cycle have been found to be highly beneficial to astronauts.
Light therapy has been trialed as a treatment for sleep disorders.
Norwegian researchers at the University of Tromsø have shown that some Arctic animals show circadian rhythms only in the parts of the year that have daily sunrises and sunsets.
In one study of reindeer,
Animals at 70°N showed circadian rhythms in the autumn,
Winter,
And spring,
But not in the summer.
Reindeer at Svalbard at 78°N showed such rhythms only in autumn and spring.
The researchers suspect that other Arctic animals as well may not show circadian rhythms in the constant light of summer and the constant dark of winter.
A 2006 study in northern Alaska found that day-living ground squirrels and nocturnal porcupines strictly maintain their circadian rhythms through 82 days and nights of sunshine.
The researchers speculate that these two rodents notice that the apparent distance between the sun and the horizon is shortest once a day.
And thus have a sufficient signal to entrain,
Adjust by.
The navigation of the fall migration of the eastern North American monarch butterfly to their overwintering grounds in central Mexico uses a time-compensated sun compass that depends upon a circadian clock in their antennae.
Circadian rhythm is also known to control mating behaviors in certain moth species,
Where females produce a specific pheromone that attracts and resets the male circadian rhythm to induce mating at night.
Although light is the primary synchronizer of the circadian rhythm through the suprachiasmatic nucleus,
Other environmental signals also influence the biological clock.
Feeding plays a key role in regulating peripheral clocks found in the liver,
Muscles,
And adipose tissues.
Time-restricted feeding can adjust these clocks by modifying light signals.
Additionally,
Physical activity affects the circadian phase,
Notably by adjusting melatonin production and body temperature.
Temperature itself is an important synchronizer,
Capable of modifying cellular circadian rhythms.
Finally,
Stress and the release of glucocorticoids influence the expression of clock genes,
Potentially disrupting biological cycles.
Integrating these factors is essential for understanding circadian rhythms beyond simple light regulation.
Plant circadian rhythms tell the plant what season it is and when to flower for the best chance of attracting pollinators.
Behaviors showing rhythms include leaf movement,
Growth,
Germination,
Stomatal gas exchange,
Enzyme activity,
Photosynthetic activity,
And fragrance emission,
Among others.
Circadian rhythms occur as a plant entrains to synchronize with the light cycle of its surrounding environment.
These rhythms are endogenously generated,
Self-sustaining,
And are relatively constant over a range of ambient temperatures.
Important features include two interacting transcription-translation feedback loops,
Proteins containing PAS domains,
Which facilitate protein-to-protein interactions,
And several photoreceptors that fine-tune the clock to different light conditions.
Anticipation of changes in the environment allows appropriate changes in a plant's physiological state,
Conferring an adaptive advantage.
A better understanding of plant circadian rhythms has applications in agriculture,
Such as helping farmers stagger crop harvests to extend crop availability and securing against massive losses due to weather.
Light is the signal by which plants synchronize their internal clocks to their environment and is sensed by a wide variety of photoreceptors.
Red and blue light are absorbed through several phytochromes and cryptochromes.
Phytochrome A,
Phi A,
Is light labile and allows germination and de-etylation when light is scarce.
Phytochromes B through E are more stable with Phi B,
The main phytochrome and seedlings grown in the light.
The cryptochrome gene is also a light-sensitive component of the circadian clock and is thought to be involved both as a photoreceptor and as part of the clock's endogenous pacemaker mechanism.
Cryptochromes 1 through 2,
Involved in blue UVA,
Help to maintain the period length in the clock through a whole range of light conditions.
The central oscillator generates a self-sustaining rhythm and is driven by two interacting feedback loops that are active at different times of day.
The morning loop consists of CCA1 and LHY,
Which encode closely related MYB transcription factors that regulate circadian rhythms in Arabidopsis,
As well as PRR7 and 9.
The evening loop consists of GI and ELF4,
Both involved in regulation of flowering time genes.
When CCA1 and LHY are overexpressed,
Plants become arrhythmic and mRNA signals reduce,
Contributing to a negative feedback loop.
Gene expression of CCA1 and LHY oscillates and peaks in the early morning,
Whereas TOC1 gene expression oscillates and peaks in the early evening.
While it was previously hypothesized that these three genes model a negative feedback loop,
In which overexpressed CCA1 and LHY repress TOC1,
And overexpressed TOC1 is a positive regulator of CCA1 and LHY,
It was shown in 2012 by Andrew Miller and others that TOC1 in fact serves as a repressor not only of CCA1,
LHY,
And PRR7 and 9 in the morning loop,
But also of GI and ELF4 in the evening loop.
This finding and further computational modeling of TOC1 gene functions and interactions suggest a reframing of the plant circadian clock as a triple negative component repressilator model rather than the positive negative element feedback loop characterizing the clock in mammals.
In 2018,
Researchers found that the expression of PRR5 and TOC1 hnRNA nascent transcripts follows the same oscillatory pattern as processed mRNA transcripts rhythmically in A.
Thaliana.
LNKs binds to the 5 region of PRR5 and TOC1 and interacts with RNAP2 and other transcription factors.
Moreover,
RVE8-LNK's interaction enables a permissive histone-methylation pattern to be modified and the histone modification itself parallels the oscillation of clock gene expression.
It has previously been found that matching a plant's circadian rhythm to its external environments,
Light and dark cycles,
Has the potential to positively affect the plant.
One of these varieties had a normal 24-hour circadian cycle.
The other two varieties were mutated,
One to have a circadian cycle of more than 27 hours and one to have a shorter than normal circadian cycle of 20 hours.
The Arabidopsis with a 24-hour circadian cycle was grown in three different environments.
One of these environments had a 20-hour light and dark cycle,
The other had a 24-hour light and dark cycle,
And the final environment had a 24-hour light and dark cycle.
The two mutated plants were grown in both an environment that had a 20-hour light and dark cycle and an environment that had a 28-hour light and dark cycle.
According to the metabolic dawn hypothesis,
Sugars produced by photosynthesis have potential to help regulate the circadian rhythm and certain photosynthetic and metabolic pathways.
As the sun rises,
More light becomes available,
Which normally allows more photosynthesis to occur.
The sugars produced by photosynthesis repress PRR7.
This repression of PRR7 then leads to the increased expression of CCA1.
On the other hand,
Decreased photosynthetic sugar levels increase PRR7 expression and decrease CCA1 expression.
This feedback loop between CCA1 and PRR7 is what is proposed to cause metabolic dawn.
Thank you for watching.
